Genetics of Childhood Obesity

Obesity is a major health problem and an immense economic burden on the health care systems both in the United States and the rest of the world. The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. Genome-wide association studies (GWAS) have revealed strongly associated genomic variants associated with most common disorders; indeed there is general consensus on these findings from generally positive replication outcomes by independent groups. To date, there have been only a few GWAS-related reports for childhood obesity specifically, with studies primarily uncovering loci in the adult setting instead. It is clear that a number of loci previously reported from GWAS analyses of adult BMI and/or obesity also play a role in childhood obesity

Translation of genome-wide association study: from genomic signals to biological insights

Since the turn of the 21st century, genome-wide association study (GWAS) have successfully identified genetic signals associated with a myriad of common complex traits and diseases. As we transition from establishing robust genetic associations with diverse phenotypes, the central challenge is now focused on characterizing the underlying functional mechanisms driving these signals. Previous GWAS efforts have revealed multiple variants, each conferring relatively subtle susceptibility, collectively contributing to the pathogenesis of various common diseases. Such variants can further exhibit associations with multiple other traits and differ across ancestries, plus disentangling causal variants from non-causal due to linkage disequilibrium complexities can lead to challenges in drawing direct biological conclusions. Combined with cellular context considerations, such challenges can reduce the capacity to definitively elucidate the biological significance of GWAS signals, limiting the potential to define mechanistic insights. This review will detail current and anticipated approaches for functional interpretation of GWAS signals, both in terms of characterizing the underlying causal variants and the corresponding effector genes

Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women

BACKGROUND: Osteoporosis is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COLIA1, the gene for collagen type Ialpha1, a bone-matrix protein. METHODS: We determined the COLIA1 genotypes SS, Ss, and ss in a population-based sample of 177

BMD loci contribute to ethnic and developmental differences in skeletal fragility across populations: Assessment of evolutionary selection pressures

Bone mineral density (BMD) is a highly heritable trait used both for the diagnosis of osteoporosis in adults and to assess bone health in children. Ethnic differences in BMD have been documented, with markedly higher levels in individuals of African descent, which partially explain disparity in osteoporosis risk across populations. To date, 63 independent genetic variants have been associated with BMD in adults of Northern-European ancestry. Here, we demonstrate that at least 61 of these variants are predictive of BMD early in life by studying their compound effect within two multiethnic pediatric cohorts. Furthermore, we show that within these cohorts and across populations worldwide the frequency of those alleles associated with increased BMD is systematically elevated in individuals of Sub-Saharan African ancestry. The amount of differentiation in the BMD genetic scores among Sub-Saharan and non-Sub-Saharan populations together with neutrality tests, suggest that these allelic differences are compatible with the hypothesis of selective pressures acting on the genetic determinants of BMD. These findings constitute an explorative contribution to the role of selection on ethnic BMD differences and likely a new example of polygenic adaptation acting on a human trait

Record of Little Ice Age sea surface temperatures at Bermuda using a growth-dependent calibration of coral Sr/Ca

Author Posting. © American Geophysical Union, 2005. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 20 (2005): PA4016, doi:10.1029/2005PA001140.Strontium to calcium ratios (Sr/Ca) are reported for a massive brain coral Diploria labyrinthiformis collected from the south shore of Bermuda and are strongly correlated with both sea surface temperature (SST) and mean annual skeletal growth rate. High Sr/Ca ratios correspond with cold SSTs and slow skeletal growth rate and vice versa. We provide a quantitative calibration of Sr/Ca to extension rate and SST along the axis of maximum growth and derive a growth-dependent Sr/Ca–SST calibration equation to reconstruct western subtropical North Atlantic SSTs for the past 223 years. When the influence of growth rate is excluded from the calibration, Sr/Ca ratios yield SSTs that are too cold during cool anomalies and too warm during warm anomalies. Toward the end of the Little Ice Age (∼1850), SST changes derived using a calibration that is not growth-dependent are exaggerated by a factor of 2 relative to those from the growth-corrected model that yields SSTs ∼1.5°C cooler than today. Our results indicate that incorporation of growth rate effects into coral Sr/Ca calibrations may improve the accuracy of SSTs derived from living and fossil corals.A Stanley Watson Foundation Fellowship (N.F.G.), and grants from NSF (OCE-0402728) and WHOI (K.A.H., A.L.C., and M.S.M.) supported this work

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes.

Background: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. Methods: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. Results: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. Conclusion: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.</p

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldWe recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism